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- Human stem cells for cardiac disease modeling and preclinical and clinical applications—are we on the road to success?Publication . Correia, Cátia; Ferreira, Anita; Fernandes, Mónica T.; Silva, Bárbara M.; Esteves, Filipa; Leitao, Helena; Bragança, José; Calado, SofiaCardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.
- Generation and characterization of two isogenic induced pluripotent stem cell lines from a young female with microcephaly carrying a compound heterozygous mutation in BUB1 genePublication . Ferreira, Anita; Calado, Sofia; Jorge, Xavier; Lange, Job de; Carvalhal, SaraMutations in the Budding uninhibited by benzimidazoles (BUB1) gene were recently associated with neurodevelopmental disorders (Carvalhal et al., 2022). Here, we describe the generation and characterization of two induced pluripotent stem cells (iPSC) clones from a young female with microcephaly. The patient carried two variants in the BUBfibroblast gene (OMIM # 602452), one (c.[2197dupG]; p.[D732fs*11]) paternally inherited and one (c.[2625+1G>A]; p.[V822_L875del] maternally inherited. The generated clones exhibit a normal karyotype (UALGi003-A) and trisomy 8 (UALGi003-B), express pluripotency markers, and differentiate into trilineage cells in vitro. These cell lines can be used to study neurodevelopment and the processes of chromosome segregation.
- Common mechanistic pathways in rare congenital syndromes with primary microcephalyPublication . Jorge, Xavier; Milagre, Ines; Ferreira, Anita; Calado, Sofia; Oliveira, Raquel; Carvalhal, SaraPrimary microcephaly is an often-seen phenotype in several rare congenital syndromes. It is characterised by a smaller brain size at birth compared to the norm. The causes of this malformation are not fully understood, but genetic testing suggests a connection with defective genes involved in mitotic regulation and proteins related to DNA repair and replication pathways. Cohesinopathies represent a group of rare syndromes, where several subtypes exhibit spontaneous railroad chromosomes and primary microcephaly. This includes Roberts Syndrome, Warsaw Breakage Syndrome and a recently characterised syndrome caused by mutations in the BUB1 gene. Currently, we are examining fibroblast cells from patients with these syndromes to identify common mechanistic pathways. In this context, we have identified a new promising candidate: Topoisomerase II alpha, a protein responsible for resolving of the DNA catenation both in the DNA replication and mitosis. Defective localisation of Topoisomerase II alpha may contribute to the observed mitotic defects in these cells. We are currently exploring the impact of these defects on brain development using reprogramming techniques to assess proper neuronal differentiation.